DCT

1:22-cv-00909

Veloxis Pharma Inc v. Accord Healthcare Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-00909, D. Del., 10/14/2022
  • Venue Allegations: Plaintiff alleges venue is proper based on Defendant Accord Healthcare’s consent to personal jurisdiction and venue, and on both Defendants’ purposeful availment of the benefits and protections of Delaware law through systematic and continuous contacts.
  • Core Dispute: Plaintiff alleges that Defendants’ filing of an Abbreviated New Drug Application (ANDA) for generic extended-release tacrolimus tablets constitutes an act of infringement of seven patents covering Plaintiff’s branded immunosuppressant drug, ENVARSUS XR®.
  • Technical Context: The patents relate to extended-release formulations and stabilized compositions of tacrolimus, an immunosuppressant drug critical for preventing organ rejection in transplant patients.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants’ May 23, 2022 and September 19, 2022 notice letters. These letters informed Plaintiff of Defendants’ ANDA filing containing Paragraph IV certifications, which assert that certain claims of the patents-in-suit are invalid and/or will not be infringed by the proposed generic products. This Supplemental Complaint was filed to add allegations concerning U.S. Patent No. 11,419,823, which issued after the original complaint was filed.

Case Timeline

Date Event
2007-05-30 Earliest Priority Date for all Patents-in-Suit
2014-04-01 U.S. Patent No. 8,685,998 Issued
2017-01-24 U.S. Patent No. 9,549,918 Issued
2019-01-01 U.S. Patent No. 10,166,190 Issued
2020-12-15 U.S. Patent No. 10,864,199 Issued
2021-09-07 U.S. Patent No. 11,110,081 Issued
2021-09-21 U.S. Patent No. 11,123,331 Issued
2022-05-23 Date of Accord Healthcare's first Notice Letter
2022-07-07 Original Complaint Filed
2022-08-23 U.S. Patent No. 11,419,823 Issued
2022-09-19 Date of Accord Healthcare's second Notice Letter
2022-10-14 Supplemental Complaint Filed

II. Technology and Patent(s)-in-Suit Analysis

No probative visual evidence provided in complaint.

U.S. Patent No. 8,685,998 - Tacrolimus for Improved Treatment of Transplant Patients

  • Patent Identification: U.S. Patent No. 8,685,998, "Tacrolimus for Improved Treatment of Transplant Patients," issued April 1, 2014 (’998 Patent).

The Invention Explained

  • Problem Addressed: The patent describes that conventional tacrolimus formulations exhibit rapid, incomplete, and variable absorption, leading to low bioavailability and significant fluctuations in blood concentration (U.S. Patent 10,864,199, col. 2:26-32). These fluctuations create a risk of high peak concentrations (Cmax) associated with neuro- and nephro-toxicity, as well as low trough concentrations that can lead to organ rejection (’199 Patent, col. 2:21-26, col. 2:52-54).
  • The Patented Solution: The invention is a method of treatment using an extended-release oral dosage form of tacrolimus that provides a specific, slow in vitro dissolution profile. This profile is designed to translate to an in vivo pharmacokinetic profile with a lower Cmax, a delayed time-to-peak (Tmax), and higher minimum concentrations, thereby improving the drug’s safety and efficacy and enabling once-daily dosing (’199 Patent, col. 3:35-53).
  • Technical Importance: By creating a more stable and predictable blood concentration profile, this approach sought to reduce the severe side effects and risk of rejection associated with conventional tacrolimus therapy, simplifying the dosing regimen for transplant patients (’199 Patent, col. 2:52-62).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶39).
  • Essential elements of claim 1 include:
    • A method of providing immunosuppressive treatment to a patient in need thereof
    • comprising orally administering once daily to the patient an extended release oral dosage form comprising tacrolimus
    • wherein the dosage form releases the tacrolimus over an extended period of time defined by a release of at the most 63.5% of the content of the active substance at the 12 hours time point
    • when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.

U.S. Patent No. 9,549,918 - Stabilized Tacrolimus Composition

  • Patent Identification: U.S. Patent No. 9,549,918, "Stabilized Tacrolimus Composition," issued January 24, 2017 (’918 Patent).

The Invention Explained

  • Problem Addressed: The patent addresses the chemical instability of tacrolimus in pharmaceutical compositions, particularly in solid dispersions where the drug molecules are more exposed (U.S. Patent 10,166,190, col. 3:53-59). This instability leads to the formation of degradation products, such as 8-epitacrolimus, which is undesirable from a regulatory and safety perspective (’190 Patent, col. 3:11-23).
  • The Patented Solution: The invention is a pharmaceutical composition that includes a "stabilizing agent," described as a metal chelating agent and an organic acid (e.g., tartaric, citric, or oxalic acid), within the tacrolimus formulation. This agent is capable of providing a pH below 7 and is intended to prevent or reduce the formation of 8-epitacrolimus and other degradation products during storage (’190 Patent, Abstract; col. 6:5-13).
  • Technical Importance: This solution provides for a tacrolimus formulation with an improved shelf-life and a more reliable impurity profile, which is critical for obtaining and maintaining regulatory approval for a pharmaceutical product (’190 Patent, col. 3:16-23).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶50).

  • Essential elements of claim 1 include:

    • A sustained release tablet comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a stabilizing agent
    • wherein the stabilizing agent is a metal chelating agent and an organic acid
    • wherein the tacrolimus is the sole active ingredient in the tablet
    • wherein the tablet comprises a sufficient amount of the metal chelating agent such that the tablet comprises less than 0.5% by weight of the 8-epitacrolimus after 12 weeks of storage at 25° C. and 60% relative humidity, based upon 100% total weight of tacrolimus.
      Multi-Patent Capsules for remaining patents-in-suit:

  • U.S. Patent No. 10,166,190: Titled "Stabilized Tacrolimus Composition," issued January 1, 2019. The patent covers a stabilized pharmaceutical composition of tacrolimus comprising a solid dispersion and a stabilizing agent, such as an organic acid, to prevent the formation of degradation products like 8-epitacrolimus (Compl. ¶17). The complaint asserts at least claim 1 and alleges that the composition of Defendants' ANDA products infringes (Compl. ¶¶61-62).

  • U.S. Patent No. 10,864,199: Titled "Tacrolimus for Improved Treatment of Transplant Patients," issued December 15, 2020. This patent covers methods for immunosuppressive treatment using an extended-release oral dosage form of tacrolimus characterized by specific in vitro dissolution profiles that result in improved pharmacokinetic parameters and allow for once-daily dosing (Compl. ¶18). The complaint asserts at least claim 14 and alleges that the use of Defendants' ANDA products will infringe (Compl. ¶¶72-73).

  • U.S. Patent No. 11,110,081: Titled "Tacrolimus for Improved Treatment of Transplant Patients," issued September 7, 2021. This patent covers methods for immunosuppressive treatment using an extended-release tacrolimus formulation with specific pharmacokinetic characteristics, such as a delayed time to maximum concentration (Tmax), which enables safe and effective once-daily administration (Compl. ¶19). The complaint asserts at least claim 1 and alleges that the use of Defendants' ANDA products will infringe (Compl. ¶¶82-83).

  • U.S. Patent No. 11,123,331: Titled "Tacrolimus for Improved Treatment of Transplant Patients," issued September 21, 2021. This patent covers methods for immunosuppressive treatment using an extended-release tacrolimus formulation defined by specific in vitro dissolution release rates over an extended period, which provides an improved pharmacokinetic profile for once-daily dosing (Compl. ¶20). The complaint asserts at least claim 1 and alleges that the use of Defendants' ANDA products will infringe (Compl. ¶¶92-93).

  • U.S. Patent No. 11,419,823: Titled "Stabilized Tacrolimus Composition," issued August 23, 2022. The patent covers a stabilized pharmaceutical composition containing tacrolimus in a solid dispersion with a stabilizing agent to reduce the formation of degradation products upon storage, ensuring the product's shelf-life stability (Compl. ¶21). The complaint asserts at least claim 17 and alleges that the composition of Defendants' ANDA products infringes (Compl. ¶¶102-103).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendants' proposed generic 0.75 mg, 1 mg, and 4 mg extended-release tablets of tacrolimus, identified as "Defendants' ANDA Products" (Compl. ¶1).

Functionality and Market Context

  • The complaint alleges that these products are generic versions of Plaintiff's ENVARSUS XR® brand tacrolimus tablets (Compl. ¶2). By filing ANDA No. 217255, Defendants have represented to the FDA that their products contain the same active ingredient, dosage form, route of administration, and strengths as ENVARSUS XR® (Compl. ¶27). The complaint further alleges that the ANDA Products are represented as bioequivalent to ENVARSUS XR® and are intended for the same approved medical indications, namely the prophylaxis of organ rejection in kidney transplant patients (Compl. ¶27, ¶23).

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a claim-chart analysis. The infringement allegations are presented in conclusory terms, stating that the proposed generic products and their use will satisfy every element of the asserted claims (e.g., Compl. ¶40, ¶51).

The narrative infringement theory for the ’998 Patent and related patents is that because Defendants' ANDA product is intended to be a bioequivalent generic of ENVARSUS XR®, its use as directed on its label will constitute a method of immunosuppressive treatment that meets the specific pharmacokinetic and in vitro dissolution profiles recited in the method claims (Compl. ¶40).

The narrative infringement theory for the ’918 Patent and related patents is that the formulation of Defendants' ANDA product itself contains the claimed combination of tacrolimus in a solid dispersion with a vehicle and a stabilizing agent, and that this composition will exhibit the stability profile (i.e., limited formation of 8-epitacrolimus) required by the claims (Compl. ¶51).

  • Identified Points of Contention:
    • Scope Questions (’998 Patent family): A central question will be whether bioequivalence to ENVARSUS XR® necessarily requires that the accused product meets the specific in vitro dissolution rate limitation of "at the most 63.5%... at the 12 hours time point" under the precise testing conditions claimed.
    • Technical Questions (’918 Patent family): The dispute may focus on whether any excipients in Defendants' formulation function as a "stabilizing agent that is a metal chelating agent and an organic acid" as construed in the context of the patent. Further, there will likely be a factual dispute over whether the accused product actually demonstrates the claimed stability against degradation into 8-epitacrolimus.

V. Key Claim Terms for Construction

  • Term (from ’998 Patent): "extended release oral dosage form... defined by a release of at the most 63.5% of the content... at the 12 hours time point"

    • Context and Importance: This term defines the core of the invention of the '998 patent family. Infringement hinges entirely on whether the accused product's dissolution profile falls within this precise numerical and conditional boundary. Practitioners may focus on this term because even minor deviations in test results or conditions could place the accused product outside the literal scope of the claim.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification discusses the goal of providing an "improved pharmacokinetic profile" and "high bioavailability" generally, which may be cited to argue that the specific numerical limit should be interpreted in light of this overall objective rather than as a rigid, absolute value, potentially opening the door for an equivalents argument (’199 Patent, col. 2:62-65).
      • Evidence for a Narrower Interpretation: The claim language recites a highly specific test protocol (USP II paddle, pH 4.5, 0.005% HEC, 50 rpm) and a precise numerical ceiling ("at the most 63.5%"). This specificity suggests the patentee intended to define the invention by this exact, measurable property, which could support a narrow construction that requires strict adherence to the recited value (’998 Patent, col. 10:35-42).

  • Term (from ’918 Patent): "stabilizing agent that is a metal chelating agent and an organic acid"

    • Context and Importance: The definition of this term is critical because infringement depends on whether an excipient in the accused formulation meets this multi-part definition. Accord has asserted non-infringement, suggesting it may argue its formulation either lacks a stabilizing agent entirely or that its chosen excipients do not possess both metal chelating and organic acid properties as understood by the patent.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification lists several examples of suitable agents, including "succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, oxalic acid, sorbic acid and mixtures thereof," which could support an interpretation covering a wide class of acidic compounds commonly used as pharmaceutical excipients (’190 Patent, col. 6:33-37).
      • Evidence for a Narrower Interpretation: The patent repeatedly emphasizes the role of the agent in providing a pH below 7 and preventing the specific degradation to 8-epitacrolimus. This functional language could be used to argue that a compound is only a "stabilizing agent" under the claim if it is proven to perform this specific function in the accused formulation, potentially narrowing the scope beyond a simple structural definition (’190 Patent, Abstract; col. 6:5-13).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement. Inducement is based on the allegation that Defendants' product labeling will instruct and encourage physicians and patients to administer the ANDA Products in a manner that directly infringes the asserted method claims (e.g., Compl. ¶43, ¶75). Contributory infringement is based on the allegation that the ANDA Products are especially adapted for an infringing use and have no substantial non-infringing use (e.g., Compl. ¶44, ¶76).
  • Willful Infringement: The complaint alleges that Defendants had knowledge of the patents-in-suit prior to filing their ANDA, which forms the basis for a claim of willful infringement (e.g., Compl. ¶47, ¶58). The filing of an ANDA with a Paragraph IV certification itself establishes knowledge of the patents listed in the Orange Book.

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of functional performance: For the '998 patent family, can Plaintiff prove that Defendants' generic product, designed to be bioequivalent, will necessarily exhibit the specific in vitro dissolution profile recited in the claims? For the '918 patent family, does Defendants' product in fact demonstrate the claimed level of chemical stability against degradation under the conditions specified in the claims?
  • A key question of definitional scope will be central to the '918 patent family: Can an excipient present in the accused formulation, which may serve other primary purposes (e.g., as a binder or filler), be properly construed as a "stabilizing agent that is a metal chelating agent and an organic acid" within the meaning of the patent claims?
  • An underlying evidentiary question will be what level of proof is required at this pre-launch stage. The dispute will turn on inferences drawn from Defendants' ANDA filing and bioequivalence data, rather than on direct testing of a commercial product, raising questions about how infringement of both composition and method claims can be established before the product is marketed.